Method for lowering intraocular pressure using phenylimino-imidazoles

ABSTRACT

2-(Trisubstituted phenylimino)-imidazole compounds also known as 2-(trisubstituted anilino)-1,3 diazacyclopentene-(2) compounds are used to lower intraocular pressure.

This is a continuation-in-part application of U.S. Ser. No. 323,369filed Nov. 20, 1981, now abandoned.

This invention relates to the treatment of glaucoma and ocularhypertension with α-adrenergics. More particularly, this inventionrelates to a method of lowering intraocular pressure (hereinafter "IOP")by the topical administration to the eye of an effective amount ofparticular 2-(trisubstituted phenylimino)-imidazoline compounds, alsoknown as 2-(trisubstituted-anilino)-1,3-diazacyclopentene-(2) compounds.

In glaucoma and ocular hypertension, the high pressure within theaffected eye presses against the blood vessels nourishing the opticnerve head and retina. When these blood vessels collapse under abnormalocular pressure, an atrophy of specific regions of the retina resultswhich ultimately is related to loss of vision and blindness. It is knownthat certain α-adrenergics, such as clonidine, also known as2-(2',6'-dichloroanilino)-1,3-diazacyclopentene-(2) and under the namingand indexing of chemical substances for Chemical Abstracts as2,6-dichloro-N-(2-imidazolidinylidene)-benzamine, are capable oflowering IOP. However, these compounds affect the central nervous systemand lower systemic blood pressure, cause drowsiness and otherundesirable side effects.

Unexpectedly, it has been discovered that the compounds of the inventionexert a selective and local ocular pharmacological action which lowersIOP without lowering systemic blood pressure. When the compounds of theinvention are applied topically to the eye they do not have to cross theblood barrier of the brain to effect IOP lowering. These compounds lowerIOP through a local or peripheral α-adrenergic action at dose levelswhich selectively lower IOP without significantly affecting the centralnervous system.

The IOP lowering action of the compounds of the invention is unexpectedbecause the locus of clonidine action has been deemed in the art to beprimarily mediated by the brain. The compounds of the inventionsurprisingly have been found to be excluded form significant absorptioninto the central nervous system or brain when administered topically atconcentrations required to lower ocular IOP. Unexpectedly, therefore, ithas been found that the compounds of the invention exert a potent IOPlowering by a local action without significantly lowering systemic bloodpressure or causing other central nervous system side effects such asdrowsiness.

It has been found that the following compounds, or pharmaceuticallyacceptable acid salts thereof, will selectively lower IOP at dosagelevels which do not significantly lower systemic blood pressure:##STR1##

I. R₁ =R₂ =methyl, ethyl, trifluoromethyl, chloro or bromo,

R₁ ≠R₂ and each=methyl, ethyl, trifluoromethyl, fluoro, chloro or bromo,

one of R₃ and R₄ is H and the other is selected from ##STR2##

R₅ =R₆ H or lower alkyl,

R₅ ≠R₆ and each=H, lower alkyl,

R₇ =H, lower alkyl 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl,

the sum of the carbon atoms in R₅ and R₆ or R₅ and R₇ being 4 or less or##STR3##

R₈ =lower alkyl;

II. R₁ --methyl, ethyl, trifluoromethyl, chloro or bromo,

R₂ =H,

R₃ is selected from ##STR4##

R₄ =methyl, chloro or bromo

R₉ =H or lower alkyl,

R₁₀ =H, lower alkyl, 2-hydroxymethyl, 2-hydroxypropyl or3-hydroxypropyl,

the sum of the carbon atoms in R₉ and R₁₀ being 4 or less.

The alkyl substituents may be straight or branched chain. Generallymethyl and ethyl derivatives are prepared because they do not easilyenter the central nervous system relative to larger alkyl groups.

The compounds in the form of the free base or a salt such as thehydrochloride or dihydrochloride preferably are formulated as aqueouseye drops having a concentration of the compounds of the invention inthe range of 0.10 to 2.0 percent by weight. The amount of the eye dropswill vary depending upon the concentration of the compounds of theinvention. Buffering agents, disinfectants and preservatives may beadded as is known in the art.

Examples of the compounds of the invention were made as follows inaccordance with the following examples.

EXAMPLE IN-[3,5-Dichloro-4-(2-imidazolidinylideneamino)-phenyl]-formamide FreeBase

N-[3,5-Dichloro-4-(2-imidazolidinylideneamino)-phenyl]formamide whichstructural is ##STR5## may be made by the following procedure.

Formic acid (35 mL, 98%) and acetic anhydride (15 mL) are stirred andheated at 50° C. for 30 minutes then cooled to 10° C. Then2,6-dichloro-N¹ -(2-imidazolidinylideneamino)-1,4-benzenediaminedihydrochloride (12 g.) is added in portions. The mixture then is heatedto 50° C. for 5 hours and then stirred for 6 hours at ambienttemperature. Ether (50 mL) is added to the stirred mixture and colorlesssolids are collected by filtration with ether washes (100 mL) to yieldafter drying 12.2 g of product with a melting point of 241°-242° C. withdecomposition and a mass spectral analysis of m/e³⁰ 272 for C₁₀ H₁₀ Cl₂N₄ O. The free base is prepared by treatment of the product with 1Nsodium hydroxide with prompt extraction by ethyl acetate. The driedethyl acetate extract is dried over anhydrous sodium sulfate andevaporated to yield a white powder (10.1 g).

EXAMPLE II 2,6-Diethyl-N-(2-imidazolidinylidene)-benzamine Free Base

2,6-Diethyl-N-(2-imidazolidinylidene)-benzamine Free Base whichstructurally is ##STR6## may be made by the following procedure.

1. 1-Acetyl-2-imidazoline may be prepared from 2-imidazoline as follows:

2-Imidazoline (60 g., 0.7 mol) is suspended in acetic anhydride (500 mL)and the mixture is heated to reflux for 30 minutes, then is reduced involume with heat and reduced pressure to a wet solid. Ethanol (250 mL)is added and a colorless solid collected by filtration. The solid is airdried to yield crude 1-acetyl-2-imidazoline (60.5 g.) having a meltingpoint of 176°-180° C. (literature melting point of 176°-177° C. asreported in J. Chem. Soc. 176 (1964)).

2. 2,6-Diethyl-N-[1-acetyl-(2-imidazolidinylidene)-benzamine may beprepared from 1-acetyl-2-imidazoline as follows:

1-Acetyl-2-imidazoline (12.6 g., 0.11 mol) in phosphorus oxychloride(140 mL) is stirred and heated to 45° C.; then 2,5-diethylbenzamine(16.5 mL, 0.10 mol) is added at a rate to maintain 50° C. After 24 hoursthe phosphorus oxychloride is evaporated with heat and reduced pressure.The resultant amber syrup then is poured onto ice (700 cc). The pH isadjusted to 12 with sodium hydroxide, and the aqueous mixture isextracted with methylene chloride (3×75 mL). The combined extracts thenare washed with a sodium hydroxide solution (50 mL) and water (2×50 mL)and dried over magnesium sulfate. Evaporation of the methylene chlorideresults in a solid which is triturated with petroleum ether (30°-60° C.boiling range, 250 mL) and collected by filtration (11.6 g., m.p.134°-137° C.). Recrystallization from cyclohexane yields2,6-diethyl-N-[1-acetyl-(2-imidazolidinylidene])-benzamine, (7.0 g.,m.p. 138°-139° C.). Elemental analysis of the product shows it has thefollowing composition: calculated foir C₁₅ H₂₁ N₃ O: C 69.46%, H 8.16%,N 16.20%; observed C 69.39%; H 8.25%, N 16.27%.

3. As the final step in the synthesis,2,6-diethyl-N-(2-imidazolidinylidene)-benzamine may be prepared from2,6-diethyl-N-[1-acetyl-(2-imidazolidinylidene)]-benzamine as follows:

2,6-Diethyl-N-[1-acetyl-(2-imidazolidinylidene)]-benzamine (4.0 g., 15.4mmol) is suspended in water (125 mL) and then is heated to reflux. After3.5 hours the resulting clear colorless solution is cooled, ice isadded, and the pH adjusted to 13 with sodium hydroxide. A whiteprecipitate forms and is collected by filtration, is washed with water(80 mL) and then dried to yield2,6-diethyl-N-(2-imidazolidinylidene)-benzamine free base white powder(3.1 g. 93%) with a melting point of 155°-157° C. and a mass spectralanalysis of m/e⁺· 217 for C₁₃ H₁₉ N₃.

EXAMPLE III 2,6-Diethyl-N-¹ -(2-imidazolidinylidene)-1,4 benzenediamineDihydrochloride

2,6-Diethyl-N-¹ -(2-imidazolidinylidene)-1,4-benzenediaminedihydrochloride which structurally is ##STR7## may be made by thefollowing procedure.

1. 2,6-Diethyl-4-nitro-N-(2-imidazolidinylidene)-benezamine may beprepared from 2,6-diethyl-N-(2-imidazolidinylidene)-benzamine (fromEXAMPLE II) as follows:

2,6-Diethyl-N-(2-imidazolidinylidene)-benzamine (4.35 g., 20 mmol) isadded to a solution of fuming nitric acid (4.5 mL) in water at 5° C.Acetic acid (20 mL) then is added to the latter solution. Sodium nitrite(310 mg., 4.5 mmol) then is added to the latter mixture and the reactionis heated to reflux. After two hours, the reaction is cooled to roomtemperature and additional sodium nitrite (310 mg.) in water (4 mL) isadded. After four additional hours at reflux the mixture is stirredovernight at room temperature. The reaction mixture is poured onto ice,the pH was adjusted to 13, and a yellow precipitate is collected byfiltration and air dried (4.5 g.). Column chromatography (silica gel;ethyl acetate, acetone, triethylamine (98:1.5:0.5)) yields2,6-diethyl-4-nitro-N-(2-imidazolidinylidene)-benzamine which istriturated after drying with petroleum ether, filtered, air dried (0.95g.) and has a mass spectral analysis of m/e⁺· 262 for C₁₃ H₁₈ N₄ O₂. 2.As the final step in the synthesis: 2,6-diethyl N¹-(2-imidazolidinylene)-1,4-benzendiamine dihydrochloride may be preparedfrom 2,6-diethyl-4-nitro-N-(2-imidazolidinylidene)-benzamine as follows:

2,6-Diethyl-4-nitro-N-(2-imidazolidinylidene)-benzamine (750 mL) isdissolved in ethanol (80 mL). Ethanol washed Raney Nickel (700 mg.) thenis added and the yellow mixture treated with hydrogen gas (45 psi)overnight to yield a colorless filtrate. The colorless filtrate isevaporated to an oil which forms needles upon standing, the needleshaving a mass spectral analysis of m/e⁺· 232 for C₁₃ H₂₀ N₄. This solidis then dissolved in methanol (50 mL), cooled to 5° C. and hydrogenchloride gas is bubbled through. After 45 minutes the solution isevaporated to yield an oil which when treated with ethyl ether gives2,6-diethyl-N'-(2-imidazolidinylidene)-1,4-benzenediaminedihydrochloride which is a colorless powder (0.72 g.) having a meltingpoint with decomposition of 250° C. Elemental analysis for thedihydrochloride salt shows it has the following composition: calculatedfor C₁₃ H₂₂ Cl₂ N₄ : C51.15%, H 7.26%, N 18.35% observed: C50.83%, H7.25%, N 18.9%.

EXAMPLE IVN-[3,5-Diethyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamideHydrochloride

N-[3,5-Diethyl-4-(2-imidazolidinylideneamino)phenyl]-acetamidehydrochloride which structurally is ##STR8## may be made by thefollowing procedure.

2,6-Diethyl-N¹ -(2-imidazolidinylidene)-1,4-benzenediaminedihydrochloride (1.9 g., 6.2 mmol), the synthesis of which is shown inEXAMPLE III, is suspended in acetic acid (15mL) and stirred at roomtemperature for 20 minutes. A solution of acetyl chloride (1.35 mL, 18.6mmol) in acetic acid (4mL) is added dropwise to the latter suspensionover 15 minutes at ambient temperature. After the addition is complete,the temperature is raised to 50° C. for 5 hours with stirring and thenis cooled.

Upon cooling, the reaction mixture is poured onto ice and the pH isadjusted to 13. The resulting solid is extracted into ethyl acetate (100mL) which is evaporated. The resulting residue is triturated withacetonitrile, is filtered and dried (1.23 g.). The resulting solid isdissolved in chloroform, is treated with charcoal, and filtered throughcelite. Evaporation of the chloroform under reduced pressure and heatyields a solid form. This solid then is dissolved in methanol andtreated with hydrogen chloride gas at 15° C. and after 45 minutes isprecipitated with ether. Recrystallization from a methanol and ethercombination yields a sample of about 1.1 g. ofN-[3,5-diethyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamidehydrochloride having a melting point of 267° C. and a mass spectralanalysis of m/e⁺· 274 for C₁₅ H₂₂ N₄ O.

EXAMPLE V 3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzenecarboxamide

3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzenecarboxamide whichstructurally is ##STR9## may be made by the following procedures.

Into a three-necked 500 mL round-bottomed flask equipped with amechanical stirrer, reflux condenser, and thermometer and charged with4-cyano,2,6-dichlorobenzamine (4 g., 0.016 m) in 30 mL of absoluteethanol is added hydrogen peroxide (9 mL of 30% in 81 mL of water) andpotassium hydroxide (4.52 g. of 30% solution). The reaction mixture isheated to a temperature of 45° C. over a thirty-minute period andmaintained at this temperature for two additional hours. At this time,the solution is cooled to 0° C. with an ice bath and filtered to yield1.8 g. of whitish crystalline material. Subsequent reduction in volumeof the filtrate results in an additional 1.1 g. of the same materialcoming out of solution for a crude yield of 2.9 g. or 68% oftheoretical. Recrystallization from water/ethanol solvent leads to alight yellow powder which has a melting point of 243°-245° C. and givesthe expected IR with double absorption in the 1700 to 1640 cm⁻¹ region.

Elemental analysis for the salt shows it has the following composition:calculated for C₁₀ H₁₀ N₄ Cl₂ : C 43.98%, H 3.69%, N 20.51%, Cl 25.96%;observed: C 43.82%, H 3.79%, N 20.39%, Cl 26.08%.

Alternatively, this example and other N- and N,N-disubstitutedcarboxamides can be prepared according to the German Offenlegungsschrift2,905,883, August 28, 1980.

EXAMPLE VI 2,6-Diethyl-N¹ -(2-imidazolidinylidene)-1,3-benzenediamineDihydrochloride

2,6-Diethyl-N¹ -(2-imidazolidinylidene)-1,3-benzenediaminedihydrochloride which structurally is ##STR10## may be made by thefollowing procedure.

1. 2,6-Diethyl-3-nitro-N-(2-imidazolidinylidene)-benezenamine may beprepared from 2,6-diethyl-N-(2-imidazolidinylidene)-benzamine asfollows:

Sulfuric acid (20 mL) is cooled to 5° C. and2,6-diethyl-N-(2-imidazolidinylidene)-benzamine (2.17 g., 10 mmol) isadded with rapid stirring. After the solid dissolves to give a darksolution, a mixture of concentrated nitric acid (0.75 mL, 12 mmol) andsulfuric acid (1.0 mL) is slowly added at 0°-5° C. Upon completeaddition, the reaction is stirred at 0°-5° C. for one hour and then ispoured onto ice (150 mL) and filtered. The filtrate is basified withsodium hydroxide (pH 13) and then is extracted with ethyl acetate (3×100mL). Chromatography (silica gel; ethyl acetate, acetone, triethylamine(92:2.5:0.5) yields a sample (1.5 g.) with a melting point of 131°-133°C. and a mass spectral analysis of m/e⁺· 262 for C₁₃ H₁₈ N₄ O₂.

2. 2,6-Diethyl-N¹ -(2-imidazolidinylidene)-1,3-benzenediaminedihydrochloride may be prepared from2,6-diethyl-3-nitro-N-(2-imidazolidinylidene)-benzamine as follows:

2,6-Diethyl-3-nitro-N-(2-imidazolidinylidene)-benzamine (1 g., 3.8 mmol)is dissolved in ethanol (80 mL) and Raney Nickel (1 g.) in ethanol (10mL) is added. The latter solution then is treated with hydrogen (45 psi)for 15 hours. The resulting almost colorless solution is filtered andevaporated to a foam which then is dissolved in methanol (50 mL),treated with charcoal and filtered. The filtrate is cooled to 5° C. andhydrochloride gas is passed through the solution for 1/2 hour. Theconcentrated solution is treated with ethyl acetate and the resultingsolid is collected by filtration. Elemental analysis of the salt showsthat it has the following composition: calculated for C₁₃ H₂₀ N₄ 2HCl: C51.15%, H 7.26%, N 18.35%; observed: C 51.06%, H 7.36%, N 18.34%.

EXAMPLE VII 2,6-Dichloro-N¹ -(2-imidazolidinylidene)-1,3-benzenediamineHydrochloride

2,6-Dichloro-N¹ -(2-imidazolidinylidene)-1,3-benzenediaminehydrochloride which structurally is ##STR11## may be made by thefollowing procedure.

1. 2,6-Dichloro-3-nitro-(2-imidazolidinyli-dene)-benzamine is preparedas follows:

2,6-Dichloro-N-(2-imidazolidinylidene)-benzamine or clonidine isprepared according to the procedure or R. Rouot et al., J. Med. Chem.,19, 1049-54 (1976). Clonidine (11.45 g, 50 mmol) is suspended withstirring in cold sulfuric acid (30 mL). Then a solution of 70% nitricacid (50 mL, 55 mmol) and concentrated sulfuric acid (50 mL) is addeddropwise with stirring over a period of thirty minutes. The reaction isstirred for two additional hours at 5°-10° C. and then poured into ice(500 cc) with stirring forming a yellow solution. Sodium hydroxidepellets (28 g.) then are added to the yellow solution. Then 5% sodiumhydroxide solution is added to the solution until the pH isapproximately 3. Then the pH adjusted solution is extracted with ethylacetate (5×500 mL). The combined ethyl acetate extracts then are driedover anhydrous sodium sulfate and then are filtered through celite. Thefiltrate is evaporated with heat and reduced pressure to yield a solidyellow foam which is triturated with hexanes and collected by filtrationto yield a product (10.2 g.) with a melting point of 154°-156.5° C. Highresolution mass spectroscopy analysis for C₉ H₈ Cl₂ N₄ O₂ : calculated274.0024, observed 274.0020, error 0.4 mmu/1.5 ppm.

2. 2,6-Dichloro-N¹ -(2-imidazolininylidene)-1, 3-benzebenzenediaminehydrochloride may be made from2,6-dichloro-nitro-N-(2-imidazolininylidene)-benamine as follows:

To a mechanically stirred suspension of2,6-dichloro-3-nitro-N-(2-imidazolidinylidene)-benzamine (5 g., 18mmol), iron powder (3.1 g., 56 mmol) and ethanol (50 mL) at reflux isadded dropwise a solution of concentrated hydrochloric acid (4.6 mL) in60% ethanol (25 mL). After the addition, the reaction is refluxed forone hour with stirring. Then potassium hydroxide (3N, 17.6 mL) is addedwhile stirring. After the latter addition, the mixture is filtered whilehot through a celite pad. The filtrate then is evaporated with heat andreduced pressure. The residue is dissolved in hot methanol treated withactivated charcoal and is refiltered through a celite pad. Again thesolvent is evaporated leaving an off-white solid (4.1 g.) with a meltingpoint of 263°-266° C. with decomposition. High resolution massspectroscopy analysis for C₉ H₁₀ Cl₂ N4: calculated 244.0282,observed244.0291, error 0.9 mmu/3.7 ppm.

German Offenlegunsggshrift 2,806,811 of Staehle et al., Aug. 23, 1979,Chemical Abstracts 92: 41944d, illustrates the following compounds:##STR12## Where: 1. R=R₃ =Cl or Br, R₂ =NH₂, R₁ =H

2. R=R₃ =Cl or Br, R₂ =H, R₁ =NH₂

3. R=R₃ =Me, R₂ =NH₂, R₁ =H

4. R=R₃ =Me, R₂ =H, R₁ =NH₂

5. R=Cl or Br, R₃ =Me, R₂, R₁ =H

6. R=Cl or Br, R₃ =H, R₂ =NH₂, R₁ =H

7. R=Cl or Br, R₃ =H, R₂ =H, R₁ =NH₂

8. R=H, R₃ =Cl or Br, R₂ =H, R₁ =NH₂

9. R=R₃ =Cl or Br, R₂ =CH₂ OH, R₁ =H

10. R=R₃ =Cl or Br, R₂ =H, R₁ =CH₂ OH

11. R=H, R₃ =Cl or Br, R₂ =CH₃, R₁ =NH₂

12. R=Cl or Br, R₃ =F, R₂ =NH₂, R₁ =H

13. R=Cl or Br, R₃ =Cl or Br, R₂ =NH₂, R₁ =F

14. R=Cl or Br, R₃ =F, R₂ =H, R₁ =NH₂

15. R=F, R₃ =Cl or Br, R₂ =H, R₁ =NH₂

Further, in any compound having the above structure discussed in GermanOffenlegungsschrift No. 2,806,811, the amine on the benzene ring of suchcompound may have the following constituents including alkyl analoguesor amides: ##STR13## In an article entitled "Synthese et reactivite dela p-aminochlonidine" by Rouot et al. in Bulletin de la Societe Chimiquede France at 79 (9-10) pt 2: 205-528 (1979) the following componentswere disclosed ##STR14##

The U.S. Pat. No. 4,094,964 to Jarrott et al. discloses the followingcompound: ##STR15##

German Offenlegungsschrift No. 2,805,775 of Stahle et al., Aug. 30 1979,Chemical Abstracts 92: 41946f illustrates the following compounds:##STR16## where

R=R₁ =Br

R=Cl, R₁ =Br

R=Cl, R₁ =Me or lower alkyl, preferably methyl or ethyl.

EXAMPLE VIII 2,6-Dichloro-N¹ -(2-imidazolidinylidene)-1,4-benzenediamineDihydrochloride

2,6-Dichloro-N¹ -(2,imidazolidinylidene-1,4-benzenediamineDihydrochloride which structurally is ##STR17## may be made by thefollowing procedure.

1. 2,6-Dichloro-1,4-benezenediamine is prepared as follows:

Wet Raney Nickel (50 g, ethanol washed) is added to2,6-dichloro-4-nitroaniline (100 g., 9.48 mol, Aldrich Chemical Co.) inethanol (800 mL) in a glass-lined pressure vessel which is charged withhydrogen (50 psi) for six hours while the reaction mixture ismechanically stirred. After the reaction and the hydrogen gas isevacuated, the reaction mixture is filtered through a celite pad,evaporated to a small volume and poured into one liter of water. Theresulting solid is collected on a filter and air dried to yield 112grams of 2,6-dichloro-1,4-benezenediamine having a melting point of118°-120° C. (literature melting point of 124°-125° C.).

2. N-(4-Amino-3,5-dichlorophenyl)-trichloro-acetamide may be preparedfrom 2,6-dichloro-1,4-benzenediamine as follows:

2,6-Dichloro-1,4-benzenediamine (225 g., 1.27 mol) is suspended inmethylene chloride (1.3 liters) containing triethylamine (245 mL, 1.7mol). After the mixture is cooled to 5° C., trichloroacetylchloride (169mL, 1.5 mol, Aldrich Chemical Co.) is added dropwise with stirring at arate to maintain 5° C. Upon complete addition, the stirred reaction isallowed to reach room temperature. After 24 hours the mixture isfiltered and the collected solid is washed with methylene chloride (700mL). The filtrate is evaporated to a small volume. A solid is collectedand washed with methylene chloride (250 mL) to yield 465 grams ofN-(4-amino-3,5-dichlorophenyl)-trichloroacetamide. The product exhibitsa mass spectral analysis of m/e⁺· 320 for C₈ H₅ Cl₅ N₂ O.

3. N-(3,5-Dichloro-4-formamidophenyl)-trichloroacetamide may be preparedfrom N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide as follows:

Acetic anhydride (600 mL, 6.4 mol) and 90% formic acid (275 mL, 5.4 mol)are heated to reflux for 45 minutes and then cooled to 5° C. TheN-(4-amino-3,5-dichlorophenyl)-trichloroacetamide (464 g., 1.44 mol) isadded to the mixed anhydride solution and mechanically stirred for 20hours at room temperature. Then the reaction mixture is poured onto ice(2 liters). When the stirred slurry reaches room temperature, it iscollected by suction filtration and washed with water (1.5 liters) anddried to constant weight yielding 348.7 grams ofN-(3,5-dichloro-4-formamidophenyl)-trichloroacetamide with a massspectral analysis of m/e⁺· 348 for C₉ H₅ Cl₅ N₂ O₂.

4. N-(3,5-Dichloro-4-dichloromethaniminophenyl)-trichloroacetamide maybe prepared from N-(3,5-dichloro-4-formamidophenyl)-trichloroacetamideas follows:

To N-(4-amino-3,5-dichloro-4-formamidophenyl-trichloroacetamide (200 g.,0.57 mol) in thionyl chloride (415 mL, 3.5 mol) at reflux is dropwiseadded sulfuryl chloride (92 mL, 1.0 mol) over a 7-hour period. Thereaction is heated for an additional 30 minutes and then allowed to stirat room temperature overnight. The reaction mixture then is reduced involume by distillation in vacuo. The cooled solid is dissolved in ethylacetate (200 mL), is treated with activated charcoal (4 g.), and isfiltered through a celite pad followed with an ethyl acetate wash. Thefiltrate is evaporated to dryness with heat and reduced pressure. Thesolid N-(3,5-dichloro-4-dichloromethaniminophenyl)-trichloroacetamide istriturated with hexanes (600 mL), filtered and dried (164.8 g., 0.41mol). A second crop of crystalline product may be collected from themother liquor (29.72 g.). The product exhibits a mass spectral analysisof m/e⁺· 400 for C₉ H₃ Cl₇ N₂ O.

5.N-[3,5-Dichloro-4-(2-imidazolidinylideneamino)-phenyl]-trichloroacetamidehydrochloridemay be made fromN-(3,5-dichloro-4-dichloromethaniminophenyl)-trichloroacetamide asfollows:

To triethylamine (300 mL) in ethyl acetate (500 mL), mechanicallystirred is dropwise added simultaneouslyN-(3,5-dichloro-4-dichloromethaniminophenyl)-trichloroacetamide (163 g.,0.4 mol) in ethyl acetate (225 mL) and ethylenediamine (40 mL, 0.74 mol)in ethyl acetate (350 mL). The addition of the former is accomplished in5 hours, the latter in 7 hours. The temperature during the additionranges from 29°-33° C. The resulting suspension is stirred for another15 hours at ambient temperature. The suspension is filtered with ethylacetate wash (200 mL) and the combined filtrates are evaporated withheat and reduced pressure. Then toluene (200 mL) is added and theproduct is evaporated to dryness. A solid forms and is dissolved inethyl acetate (800 mL) which then is cooled to 0° C. Hydrogen chloridegas is bubbled into the solution at less than 10° C. A white solidprecipitate is collected by filtration, washed with ethyl acetate (200mL) and dried to yieldN-[3,5-dichloro-4-(2-imidazolidinylideneamino)-phenyl]-trichloroacetamidehydrochloride (180 g.) with a mass spectral analysis of m/e⁺· 388 forC₁₁ H₉ N₄ Cl₅ O.

6. As the final step in the synthesis, 2,6-dichloro-N¹-(imidazolidinylideneamino)-1,4-benzenediamine dihydrochloride may beprepared fromN-[3,5-dichloro-4-(2-imidazolidinylideneamino)-phenyl]-trichloroacetamidehydrochloride as follows:

To a solution ofN-[3,5-dichloro-4-(2-imidazolidylideneamino)-phenyl]-trichloroacetamidehydrochloride (262.5 g.) in methanol (750 mL) is added methanolsaturated with anhydrous ammonia (750 mL). The solution is stirred atroom temperature for four days under anhydrous conditions. The solutionthen is evaporated to dryness and the crystalline product trituratedwith ethyl ether (4×400 mL). The crystals are collected and dried toyield 137.5 g. of product. The crystals then are dissolved in methanol(1.8 liters), the solution is cooled to 10° C. and hydrogen chloride gasthen is passed through the stirred solution at such a rate as tomaintain the temperature below 15° C. After an hour a solid is collectedand washed with cold methanol. Reprecipitation from methanol/ether anddrying yields the dihydrochloride salt as a colorless or white powder(124.6 g.). Elemental analysis of the product shows that it has thefollowing composition: calculated for C₉ H₁₂ Cl₄ N₄ : C 33.94%, H 3.80%,N 17.62%; observed: C 33.79 %, H 4.00%, N 17.44%.

EXAMPLE IX 3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzoic acidethyl ester

3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzoic acid ethyl esterwhich structurally is ##STR18## may be made by the following procedure.

1. Preparation of 4-amino-3,5-dichlorobenzoic acid ethyl ester:

Reaction of 4-aminobenzoic acid ethyl ester (20.7 g., 0.125 m. AldrichChem. Co.) with 430 mL of 6N HCl and 30% H₂ O₂ (25.3 mL, 0.25 m) leadsto the formation of 27.1 g. of reddish brown crystalline solid with amelting point of 46°-49.5° C.

2. 3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzoic acid ethyl estermay be made from 4-amino -3,5-dichlorobenzoic acid ethyl ester asfollows:

Following the procedure in Rouot et al., in J. Med. Chem., 19, 1049(1976), 4-amino-3,5-dichlorobenzoic acid ethyl ester (70.2 g., 030 m) isreacted with the product from acetic anhydride (61.3 g., 0.60 m) andformic acid (34.5 g., 0.75 m) to yield the desired3,5-dichloro-4-formamidobenzoic acid ethyl ester (62.0 g., 0.237 m) incrude yield of 79% with a melting point of 168°-170° C. Reaction of thiscrude (16.35 g., 0.062 m) with a mixture of thionyl chloride (55.4 g.,0.47 m) and sulfuryl chloride (3.4 g., 0.062 m) leads to the desired3,5-dichloro-4-dichloromethaniminobenzoic acid ethyl ester (14.65 g., 46mmol) which distills at 105° C. at 250 mm of Hg after standard workup.It should be noted that this material may solidify on standing. Finally,this distilled dichloromethamine (4.35 g., 0.0138 m) is reacted withethylene diamine (1.66 g., 0.0276 m), and 10 mL of triethylamine inapproximately 25 mL of ethyl acetate for 10 hours. An immediate whiteprecipitate is noted, but stirring is continued overnight to ensurecomplete reaction. This reaction mixture then is vacuum filtered toyield 5.35 g. of white powder (which is greater than 100% yield, but isprobably due to the fact that, in addition to the desired compound,triethylamine hydrochloride as well as the hydrochloride of the desiredcompound are present at this stage). Recrystallization of the whitepowder from absolute ethanol produced a white crystalline solid (2.3 g.,0.0076 m) in a yield of 55% with a melting point of 238°-240° C. Thiscompound demonstrates the expected IR absorptions at 3380 (sharp), 3150(broad), 1710 (sharp), 1660 (sharp and most intense), 1580 (sharp), 1275(sharp), 1105 cm⁻¹ (sharp).

Elemental analysis of the product shows that it has the followingcomposition: calculated for C₁₂ H₁₃ N₃ Cl₂ O₂ : C 47.70%, H 4.34%, N13.91%, Cl 23.47%, observed: C 47.66%, H 4.41%, N 13.88%, Cl 23.82%.

EXAMPLE X 3.5-Dichloro-4-(2-imidazolidinylideneamino)-benzenemethanol

This compound is structurally ##STR19## and may be made by thefollowing:

This compound is synthesized by direct reduction of the correspondingester of EXAMPLE IX, or the compound also can be prepared according toStahle, Koeppe, Kummer, Holfke and Pichler, Boehringer C. H. Sohn Ger.Offen. No. 2,806,811, Aug. 23 1979. Thus,3,5-dichloro-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester(3.03 g., 0.01 m) is dissolved in 70 mL of dry benzene in a three-necked250 mL round-bottomed flask equipped with nitrogen inlet, magneticstirrer, addition funnel, reflux condenser, and thermometer. Twelve mlof a 24% solution of diisobutyl aluminum hydride (3.0 g., 0.021 m) intoluene is added over 30 minutes and the mixture heated for anadditional 2-hour period while maintaining the temperature at 45° C.Standard work up leads to 1.6 g (61%) of yellowish crystalline materialwith a melting point of 195°-200° C. Subsequent recrystallization fromabsolute ethanol led to an almost white crystalline material with amelting point of 212°-214° C. The IR spectrum of this compound wasconsistent with the desired compound.

Elemental analysis of the product shows that it has the followingcomposition: calculated for C₁₀ H₁₁ N₃ Cl₂ O: C 46.17%, H 4.26%, N16.15%, Cl 27.26%; observed: C 46.11%, H 4.27%, N 16.13%, Cl 27.48%.

EXAMPLE XI 3,5-Dichloro-4-(2-imidazolidinylideneamino)-benzoic acid

This compound is structurally ##STR20## and may be made by the followingprocedure.

This compound is synthesized by acid hydrolysis of the correspondingester of EXAMPLE IX. Thus, a solution of3,5-dichloro-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester(4.5 g., 0.015 m) in 10 mL of 6N HCl is added to 150 ml of 10% HCl at atemperature of 70° C. in a 250 mL three-necked round-bottomed flaskequipped with a reflux condenser and magnetic stirrer. The resultingsolution was heated to reflux for 1.5 hours, cooled to causeprecipitation, and vacuum filtered to yield 4.0 g. (86%) of a crudewhite powder, which did not melt below 320° C. Recrystallization of thismaterial from absolute ethanol led to a white powder which did not meltbelow 320° C. and which had an IR spectrum consistent with the titlecompound.

Anal. Calcd. for C₁₀ H₁₀ N₃ Cl₃ O₂ : C, 38.67%; H, 3.25%; N, 13.53%; Cl,34.25%. Found: C, 38.78%; H, 3.30%; N, 13.42%; Cl, 34.10%.

EXAMPLE XII 4-Cyano-2,6-dichloro-N-(2-imidazolidinylidene)-benzamineHydrochloride

This compound is structurally ##STR21## and may be made by the followingprocedure.

1. Preparation of 4-cyano-2,6-dichlorobenzamine.

Reaction of 4-cyanobenzamine (10 g., 0.085 m, Aldrich Chem. Co.) with292 ml of 6N HCl and 30% H₂ O₂ (17.2 mL, 0.17 m) led to the formation ofa white crystalline compound with a melting point of 113°-115° C. Theyield of this compound was 12.3 g.

2. 4-Cyano-2,6-dichloro-N-(2-imidazolidinylidene)-benzamine may beprepared from 4-cyano-2,6-dichlorobenzamine as follows:

4-Cyano-2,6-dichlorobenzamine (8.00 g., 0.043 m) is converted to thecorresponding N-(4-cyano-2,6-dichlorophenyl)-formamide (7.05 g., 0.033m) for a 77% yield of a white powder with a melting point of 198°-200°C. Treatment of this formamide (4.3 g., 0.020 m) with thionyl chloride(35.7 g., 0.30 m) and sulfuryl chloride (4.10 g., 0.03 m) yieldsN-(4-cyano-2,6-dichlorophenyl)-dichloromethanimine (3.9 g., 0.0145 m)which is obtained by distillation at 110° C. at 250 mmHg for a yield of73%. The product, which solidifies readily after the solvent andreactants have been completely stripped from the reaction mixture, iswashed with hexanes. The dichloromethanimine (3.0 g., 0.011 m) isreacted with ethylene diamine and leads tothe title compound (2.3 g.,0.0089 m) as a yellow white powder in a crude yield of 81% with amelting point of 245°-250° C. Subsequent recrystallization from absoluteethanol leads to fluffy, cream-colored needles having a melting point of255°-258° C. The IR spectrum of this compound was consistent with thetitle compound with prominent absorptions at 2200 and 1650 cm⁻¹.

Elemental analysis of the product shows that it has the followingcomposition: calculated for C₁₀ H₈ N₄ Cl₂ : C 47.08%, H 3.16%, N 21.96%,Cl 27.79%; observed: C 46.93%, H 3.32%, N 21.71%, Cl 27.88%.

EXAMPLE XIII 6-Chloro-N¹-(2-imidazolidinylidene)-4-methyl-1,3-benzenediamine Dihydrochloride

6-Chloro-N¹ -(2-imidazolidinylidene)-4-methyl-1,3-benzenediaminedihydrochloride which structurally is ##STR22## may be made by thefollowing procedure.

1. Preparation of N-(2-chloro-4-methylphenyl)-formamide is as follows:

Acetic anhydride (50 mL, 0.53 mol) and 97-100% formic acid (21.5 mL,0.45 mol) are reacted to 50° C. for 15-20 minutes with stirringwhereupon the solution is cooled to 0° C. 2-chloro-4-methylbenzamine(35.3 g., 30.7 mL, 0.25 mol, Aldrich Chem. Co.) then is added dropwiseover 15 minutes with stirring. Then the stirred solution is heated to50° C. for 7 hours. The solution is evaporated to dryness with heat andreduced pressure and the residue recrystallized from toluene (150 mL) toyield colorless crystals.

2. N-(2-Chloro-4-methylphenyl)-dichloromethanimine may be prepared fromN-(2-chloro-4-methylphenyl)-formamide as follows:

To N-(2-chloro-4-methylphenyl)-formamide (15.0 g., 88 mmol) in thionylchloride (78.5 g., 48 mL, 0.66 mmol) is added dropwise sulfuryl chloride(11.9 g., 7.1 mL, 88 mmol). The stirred solution is heated for 9 hourswith a dry ice condenser affixed. Then the reaction solution isconcentrated by heat and reduced pressure. Distillation (55°-65° C. at100 mm Hg) yields a product (16.0 g.).

3. 6-Chloro-N-(2-imidazolidinylidene)-4-methyl benzamine may be preparedfrom N-(2-chloro-4-methylphenyl)-dichloromethanimine as follows:

To triethylamine (55 mL) in ethyl acetate (40 mL) mechanically stirredis dropwise added stimultaneouslyN-(2-chloro-4-methylphenyl)-dichloromethanimine (16 g., 72 mmol) inethyl acetate (20 mL) and ethylenediamine (8.6 g., 9.6 mL, 144 mmol) inethyl acetate (20 mL) over a period of 50 minutes. The reaction mixtureis allowed to stir for an additional 20 hours at ambient temperature.The mixture is filtered and the filtrate is evaporated with heat andreduced pressure. The residue is triturated with ethyl acetate andcollected by filtration and air dried (4.2 g.). The layer chromatographyon silica gel (chloroform, methanol), concentrated ammonium hydroxide:8.5, 1.5., 2 drops) showed the product at Rf=0.5. The product exhibits amass spectral analysis of m/e⁺ ·209 for C₁₀ ClH₁₂ N₃.

4. 6-Chloro-N-(2-imidazolidinylidene)-4-methyl-3-nitro-benzamine may bemade from 6-chloro-N(-2-imidazolidinylidene)-4-methyl-benzamine asfollows:

To 6-chloro-N-(2-imidazolidinylidene)-4-methyl-benzamine (1.0 g., 4.8mmol) in concentrated sulfuric acid (5 mL) at 5° C. is added dropwisewith stirring to a solution of concentrated sulfuric acid (0.26 mL) and70% nitric acid (0.33 mL) during a 15 minute period. After thirtyminutes the darkened reaction mixture is poured onto ice, basified to pH10 with ammonium hydroxide and extracted with ethyl acetate (4×50 mL).The combined extracts are dried over anhydrous sodium sulfate.Evaporation with heat and reduced pressure yields a yellow powder (1.1g.). Recrystallization from toluene yields a yellow solid (0.4 g.) whichgives a single spot on thin layer chromatography with silica gel(chloroform, methanol, concentrate ammonium hydroxide: 9, 1, 2 drops)Rf=0.73. The product exhibits a mass spectral analysis of m/e⁺ ·254 forC₁₀ H₁₁ Cl N₄ O₂.

5. 6-chloro-N¹ -(2-imidazolidinylidene)-4-methyl-1,3-benzenediaminedihydrochloride may be made from6-chloro-N-(2-imidazolidinylidene)-4-methyl-3-nitro-benzamine asfollows:

To a mechanically stirred suspension of6-chloro-N-(2-imidazolidinylidene)-4-methyl-3-nitrobenzamine (0.5 g., 2mmol), iron powder (0.65 g., 6 mmol) and 50% ethanol (10 mL) is addeddropwise hydrochloric acid (1.0 mL). The reaction mixture then isrefluxed for one hour and then sodium hydroxide is added. The reactionmixture is filtered and the solid washed with ethanol. The filtrate isevaporated to dryness, dissolved in methanol and filtered. The filtrateis evaporated again, redissolved in methanol (30 mL) and hydrogenchloride gas is bubbled through the solution. After evaporation thesolid is titrated with ether (3×30 mL) yielding a product afterrecrystallization from methanol (0.25 g.) with a melting point of243°-248° C. with decomposition. The product exhibits a mass spectralanalysis of m/e⁺ ·224 for C₁₀ H₁₃ ClN₄. Elemental analysis of theproduct shows: C₁₂ H₁₅ Cl₂ N₄. 1/2 H₂ O: calculated C 39.17%, H 5.26%, N18.27%; observed: C38.79%, H 5.09%, N 17.95%.

EXAMPLE XIV 2,6-Dichloro-N¹ -(2-imidazolidinylidene)-N⁴, N⁴-dimethyl-1,4-benzenediamine Dihydrochloride

2,6-Dichloro-N¹ -(2-imidazolidinylidene) N⁴, N⁴-dimethyl-1,4-benzenediamine dihydrochloride which PG,31 structurally is##STR23## may be made by the following procedure. 2,6-dichloro-N¹-(2-imidazolidinylidene)-N⁴, N⁴ -dimethyl-1,4-benzenediaminedihydrochloride was prepared according to the general procedure of R.Rouot and G. Leclerc, Bull. Soc. Chim. Fr., 1979 (pt. 2), 520-28 withthe exception that the free base was converted to the dihydrochloridesalt. The free base of 2,6 dichloro-N¹ -(2-imidazolidinylidene)-N⁴,N⁴-dimethyl-1,4-benzenediamine (0.5 g.) after chromatographic purificationwas dissolved in methanol (40 mL) and cooled to 5°-10° C. in an ice bathand hydrogen chloride gas was bubbled through the solution. The solutionwas treated with powdered charcoal (1 g.), filtered through a celitepad, evaporated to dryness and triturated with ether to yield a whitepowder (1.7 g.) with a melting point of 275°-277° C. with decomposition.NMR (CDCl₃, TMS): 2.85 (amine methyls, 6H, S), 3.50 (ethylene; 4H, S)6.67 (aromatic, 2H, S). Mass spectral analysis m/e⁺ ·272 for C₁₁ H₁₄ Cl₂N₄.

In addition to the examples set forth herein, compounds contemplated foruse in the present invention include the following free bases andpharmaceutically acceptable salts:

2,6-Dibromo-N¹ -(2-imidazolidinylidene)-1,4-benzenediamine having thestructure: ##STR24## 2,6-Dibromo-N¹-(2-imidazolidinylidene)-1,3-benzenediamine having the structure:##STR25##N-[3,5-Dibromo-4-(2-imidazolidinylideneamino)-phenyl]-acetamide havingthe structure: ##STR26##N-[2,4-Dibromo-3-(2-imidazolidinylideneamino)-phenyl]-acetamide havingthe structure: ##STR27##3,5-Dibromo-4-(2-imidazolidinylideneamino)-phenol and phenolic estersthereof having the structure: ##STR28## 2,6-Ditrifluoromethyl-N¹-(2-imidazolidinylidene)-1,4-benzenediamine having the structure:##STR29## 2,6-Ditrifluoromethyl-N¹-(2-imidazolidinylidene)-1,3-benzenediamine having the structure:##STR30##N-[3,5-Ditrifluoromethyl-4(2-imidazolidinylideneamino)-phenyl]-acetamidehaving the structure: ##STR31## 2,6-Dimethyl-N¹-(2-imidazolidinylidene-1,4-benzenediamine having the structure:##STR32## 2,6-Dimethyl-N¹ -(2-imidazolidinylidene-1,3-benzenediaminehaving the structure: ##STR33##N-[3,5-Dimethyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamide havingthe structure: ##STR34##N-[2,4-Dimethyl-3-(2-imidazolidinylideneamino)-phenyl]-acetamide havingthe structure: ##STR35##N-[2,4-Diethyl-3-(2-imidazolidinylideneamino)-phenyl]-acetamide havingthe structure: ##STR36##3,5-Dimethyl-4-(2-imidazolidinylideneamino)-phenol and phenolic estersthereof having the structure: ##STR37##3,5-Diethyl-4-(2-imidazolidinylideneamino)-phenol and phenolic estersthereof having the structure: ##STR38##3,5-Dibromo-4-(2-imidazolidinylideneamino)-phenol and phenolic estersthereof having the structure: ##STR39## 2,6-Dichloro-N¹-(2-imidazolidinylidene)-N⁴ -methyl-1,4-benzenediamine having thestructure: ##STR40## 2,6-Dibromo-N¹ -(2-imidazolidinylidene)-N⁴-methyl-1,4-benzenediamine having the structure: ##STR41##2,6-Dimethyl-N¹ -(2-imidazolidinylidene)-N⁴ -methyl-1,4-benzenediaminehaving the structure: ##STR42## 2,6-Diethyl-N¹-(2-imidazolidinylidene)-N⁴ -methyl-1,4-benzenediamine having thestructure: ##STR43## 2,6-Dibromo-N⁴, N⁴ -dimethyl-N¹-(2-imidazolidinylidene)-1,4-benzenediamine having the structure:##STR44## 2,6-Dimethyl-N⁴, N⁴ -dimethyl-N¹-(2-imidazolidinylidene)-1,4-benzenediamine having the structure:##STR45## 2,6-Diethyl-N⁴, N⁴ -dimethyl-N¹-(2-imidazolidinylidene)-1,4-benzenediamine having the structure:##STR46## N⁴, N⁴ -Dimethyl-N¹-(2-imidazolidinylidene)-2,6-ditrifluoromethyl-1,4-benzenediamine havingthe structure: ##STR47##N-[3,5-Dichoro-4-(2-imidazolidinylideneamino)-phenyl]-N-methyl-acetamidehaving the structure: ##STR48## N-[3,5-Dibromo-4-(2-imidazolidinylideneamino)-phenyl]-N-methyl-acetamide having thestructure: ##STR49##N-[3,5-Diethyl-4-(2-imidazolidinylideneamino)-phenyl]-N-methyl-acetamidehaving the structure: ##STR50##3,5-Dichloro-4-(2-imidazolidinylideneamino)-benezenemethanol and estersthereof having the structure: ##STR51##N[3-bromo-5-chloro-4-(2-imidazolidinylideneamino)-phenyl]-acetamidehaving structure: ##STR52##N-[3-bromo-5-chloro-4-(2-imidazolidinylideneamino)-phenyl]-N-methyl-acetamidehaving the structure: ##STR53##3-Bromo-5-chloro-4-(2-imidazolidinylideneamino)-phenol and phenolicesters thereof having the structure: ##STR54##3,5-Dibromo-4-(2-imidazolidinylideneamino)-benzenecarboxamide having thestructure: ##STR55##3,5-Dichloro-4-(2-imidazolidinylideamino)-benzene-N,N-dimethyl-carboxamidehaving the structure: ##STR56##3,5-Dibromo-4-(2-imidazolidinylideneamino)-benzoic acid and alcoholesters thereof having the structure: ##STR57##3,5-Dibromo-4-(2-imidazolidinylideneamino)-benzenemethanol and estersthereof having the structure: ##STR58##

Other compounds contemplated by the invention are:

A. 3,5-Dichloro-4(2-imidazolidinylideneamino)-benzoic acid ethyl esterhaving the structure: ##STR59## B.3-Chloro-5-ethyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl esterhaving the structure: ##STR60## C.3,5-Diethyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl esterhaving the structure: ##STR61## D.N-[3-chloro-5-ethyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamidehaving the structure: ##STR62## E. 2-chloro-6-ethyl-N¹-(2-imidzolidinylidene)-1,4-benzenediamine having the structure:##STR63## and pharmaceutically acceptable salts thereof.

The efficacy of several 2-(trisubstituted anilino)-1,3diazacyclopentene-(2) compounds shown in Table I in lowering IOP withoutaffecting the central nervous system using clonidine as a control wastested by the following biological procedure. (A to E)

The data from the hereinafter described tests is illustrated in Table I.

A. Rhesus Monkey--Laser Model

Ocular hypertension was produced in adult Rhesus monkeys (4) via anargon laser photocoagulation of trabecular meshwork in the eye. Thetreated eye (only one is lasered) was allowed to heal and the IOPstabilized after about six weeks. Tests were performed by topicaladministration of one drop of a 0.5% solution of the test agent to theKetamine anesthetized Rhesus monkey's eye. The IOP charge was recordedby an Alcon Applanation Phneumatonograph. The peak effect was recordedas a percentage change in the hypertensioned eye versus the IOP value ofthe same eye recorded at the same hour the previous day.

B. Normal Rabbit Model

To determine the IOP reduction efficacy of the anti-glaucoma drugs ofthe invention in normal albino rabbits the following was done.

New Zealand albino rabbits (12) were acclimatized in restraining boxesfor thirty minutes. Alcaine/saline (1:5) was applied to the rabbit eyesand baseline IOP in mm Hg pressure were measured using an AlconLaboratory Applanation Phneumatonograph. Then thirty minutes later, thecoded test substance versus a coded saline control was administered as a50 ul drop to one eye, six animals in each group. The treatment effectswere measured as a function of time. Mean IOP and mean change in IOP foreach hourly reading was recorded. The effect cited is a peak percentageeffect versus the external control test group.

C. The "Steroid" Rabbit Model

Biological procedures for measuring IOP effects of drugs in the"steroid" rabbit model are given in B. L. Bonomi and L. Tomayzol,Invest. Ophthal 15, 781,784 (1976) and L. Bonomi et al., Albrect GraefesArch. Ophthal., 209, 73, 89. Luciano Bonomi et al., Albrect GraefesArch. Ophthal., 219, 1, 8, (1979) shows the model works for knownantiglaucoma drugs. In the experiments shown in Table I, a drop of thedrug was administered to one eye of the subject rabbit and the IOP inthe treated eye was monitored as a function of time.

D. 20% Blood Pressure Decrease In the Rat

Six Sprague-Dawley rats (6 per test group at 200-400 g.) areanesthetized (65 mg/kg sodium pentobarbital) and placed on a heatingpad. The femoral artery was cannulated and hydrolically connected to apressure transducer and Grass Model 7 recorder. A fifteen minute bloodpressure reading was recorded. A buffered test agent was givenintravenously in a small volume (i.e., 0.1 mL). The test agent effect onblood pressure was then recorded. The mean dose calculated to lowerblood pressure 20% in the rat is given in ug/kg.

E. Potentiation of Hexobarbital Induced Anesthesia

Concomitant intraparateneal administration of the test drug andhexobarbital to mice will result in an increase in the duration ofanesthesia as compared to hexobarbital alone, if the test compound hassedative activity. This potentiation can be used as a relative measureof central nervous system effect (sedative activity) for comparison oftest compounds. The endpoint of anesthesia was recorded as the recoveryof the "righting reflex".

                  TABLE I                                                         ______________________________________                                        IOP Lowering Data                                                             (Drop In Intraocular Pressure                                                 After Topical Administration of Drug)                                         ______________________________________                                                                       (B)                                                              (A)          50 μL 1%                                                      50 μL 0.5%                                                                              topical                                                          topical      Normal                                                           Laser-Monkey Rabbit                                                           % IOP        % IOP                                          ______________________________________                                        R.sub.1 = R.sub.2 = Cl;                                                                         -32.0%       -13.9%                                         R.sub.3 = R.sub.4 = H                                                         2,6-Dichloro-N--(2-                                                           imidazolidinylidene)-                                                         benezamine Free Base                                                          R.sub.1 = R.sub.2 = Cl;                                                                         -21.0%       -1.3%                                          R.sub.3 = H, R.sub.4 = NH.sub.2                                               2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-1,4-                                                     benzenediamine Dihydro-                                                       chloride                                                                      R.sub.1 = R.sub.2 = Cl;                                                                         -26.0%       -15.6%                                         R.sub.3 = H, R.sub.4 = NCOH                                                   N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-formamide Free Base                                                   R.sub.1 = R.sub.2 = Cl;                                                                          -4.0%       -19.0%                                         R.sub.3 = H, R.sub.4 = NCOCH.sub.3                                            N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-acetamide Hydrochloride                                               R.sub.1 = R.sub. 2 = Cl;                                                                        -23.0%       -7.4%                                          R.sub.3 = H, R.sub.4 = --OH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    phenol Hydrochloride                                                          R.sub.1 = R.sub.2 = Cl;                                                                         --           0.0%                                           R.sub.3 = --NH.sub.2, R.sub.4 = H                                             2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Hydrochloride                                                                 R.sub.1 = R.sub.2 = Cl;                                                                           -17%       0.0%                                           R.sub.3 = H, R.sub.4 = --CH.sub.2 --OH                                        3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenemethanol                                                               Hydrochloride                                                                 R.sub.1 = R.sub.2 = Cl;                                                                         --           -4.5%                                          R.sub.3 = H, R.sub.4 = COOH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylidene                                                           amino)-benzoic Acid                                                           R.sub.1 = R.sub.2 = Cl;                                                                         --           -5.6%                                          R.sub.3 = H, R.sub.4 = CO.sub.2 C.sub.2 H.sub.5                               3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzoic Acid Ethyl Ester                                                      R.sub.1 = R.sub.2 = Cl;                                                                         --           -10.2%                                         R.sub.3 = H, R.sub. 4 = N(CH.sub.3).sub.2                                     2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-N.sup.4, N.sup.4-                                        dimethyl-1,4-benzene-                                                         diamine Dihydrochloride                                                       R.sub.1 = R.sub.2 = ethyl;                                                                      --           --                                             R.sub.3 = H, R.sub.4 = H                                                      2,6-Diethyl-N--(2-                                                            imidazolidinylidene)-                                                         benzamine Free Base                                                           R.sub.1 = R.sub.2 = ethyl;                                                                      --           --                                             R.sub.3 = H, R.sub.4 = NH.sub.2                                               2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,4-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = ethyl;                                                                      --           --                                             R.sub.3 = H, R.sub.4 = --NCOCH.sub.3                                          N--[2,6-Diethyl-4-(2-                                                         imidazolidinylideneamino)-                                                    phenyl]-acetamide                                                             Hydrochloride                                                                 R.sub.1 = R.sub.2 = ethyl;                                                                      --           --                                             R.sub.3 = --NH.sub.2, R.sub.4 = H                                             2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = Cl;                                                                         --           -2.3%                                          R.sub.3 = H, R.sub.4 = --CN                                                   4-Cyano-2,6-dichloro-                                                         N--(2-imidazolidinylidene)-                                                   benzamine                                                                     R.sub. 1 = R.sub.2 = Cl;                                                                        --           --                                             R.sub.3 = H, R.sub.4 = --CONH.sub.2                                           3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenecarboxamide Free Base                                                  R.sub.1 = Cl; R.sub.2 = H; R.sub.3 = NH.sub.2 ;                               R.sub.4 = CH.sub.3                                                            6-Chloro-N.sup.1 = (2-                                                        imidazolidinylidene)-                                                         4-methyl-                                                                     1,3-benzenediamine                                                            Dihydrochloride                                                               ______________________________________                                                                       (D)                                                              (C)          Dose - 50 μL 0.5% 50 μl/kg                                 topical      20% b.p.                                                         Steroid Rabbit                                                                             Decease                                                          % IOP        Rat                                            ______________________________________                                        R.sub.1 = R.sub.2 = Cl;                                                                         -27.0%       4.8                                            R.sub.3 = R.sub.4 = H                                                         2,6-Dichloro-N--(2-                                                           imidazolidinylidene)-                                                         benezamine Free Base                                                          R.sub.1 = R.sub.2 = Cl;                                                                         -25.0%       50.0                                           R.sub.3 = H, R.sub.4 = NH.sub.2                                                                 .sup. -25.0%.sup.2                                                            .sup. -21.0%.sup.3                                          2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-1,4-                                                     benzenediamine Dihydro-                                                       chloride                                                                      R.sub.1 = R.sub.2 =  Cl;                                                                        -30.0%       30.0                                           R.sub.3 = H, R.sub.4 = NCOH                                                   N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-formamide Free Base                                                   R.sub.1 = R.sub.2 = Cl;                                                                         -30.0%       18.0                                           R.sub.3 = H, R.sub.4 = NCOCH.sub.3                                            N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-acetamide Hydrochloride                                               R.sub.1 = R.sub.2 = Cl;                                                                          -4.0%       38.0                                           R.sub.3 = H, R.sub.4 = --OH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    phenol Hydrochloride                                                          R.sub.1 = R.sub.2 = Cl;                                                                         -25.0%       16.0                                           R.sub.3 = --NH.sub.2 , R.sub.4 = H                                            2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Hydrochloride                                                                 R.sub.1 = R.sub.2 = Cl;                                                                         -26.0%       190.0                                          R.sub.3 H, R.sub.4 = --CH.sub.2, --OH                                         3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenemethanol                                                               Hydrochloride                                                                 R.sub.1 --R.sub.2 = Cl                                                                          -19.9%       50,000.0                                       R.sub.3 = H, R.sub.4 = COOH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylidene                                                           amino)-benzoic Acid                                                           R.sub.1 = R.sub.2 = Cl;                                                                         -20.7%       27,000.0                                       R.sub.3 = H, R.sub.4 = CO.sub.2 C.sub.2 H.sub.5                                                 .sup.  -14.0.sup.3                                          3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzoic Acid Ethyl Ester                                                      R.sub.1 = R.sub.2 = Cl;                                                                         --           1,000.0                                        R.sub.3 = H, R.sub.4 = N(CH.sub.3).sub.2                                      3,6-Dichloro-N.sup.1 --2                                                      imidazolidinylidene)-N.sup.4, N.sup.4-                                        dimethyl-1,4-benzene-                                                         diamine Dihydrochloride                                                       R.sub.1 = R.sub.2 = ethyl;                                                                       11.3%       19.0                                           R.sub.3 = H, R.sub.4 = H                                                      2,6-Diethyl-N--(2-                                                            imidazolidinylidene)-                                                         benzamine Free Base                                                           R.sub.1 = R.sub.2 = ethyl;                                                                      --           10.0                                           R.sub.3 = H, R.sub.4 = NH.sub.2                                               2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,4-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = ethyl;                                                                      --           130.0                                          R.sub.3 = H, R.sub.4 = --NCOCH.sub.3                                          N--[2-6-Diethyl-4-(20                                                         imidazolidinylideneamino)-                                                    phenyl]-acetamide                                                             Hydrochloride                                                                 R.sub.1 = R.sub.2 = ethyl;                                                                      --           100.0                                          R.sub.3 = --NH.sub.2, R.sub.4 =  H                                            2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = Cl;                                                                         --           8,300.0                                        R.sub.3 = H, R.sub.4 = --CN                                                   4-Cyano-2,6-dichloro-                                                         N--(2-imidazolidinylidene)-                                                   benzamine                                                                     R.sub.1 = R.sub.2 = Cl;                                                                         --           --                                             R.sub.3 = H, R.sub.4 = --CONH.sub.2                                           3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenecarboxamide Free Base                                                  R.sub.1 = Cl; R.sub.2 = H; R.sub.3 = NH.sub.2 ;                               R.sub.4 = CH.sub.3                                                            6-Chloro-N.sup.1 = (2-                                                        imidazolidinylidene)-                                                         4-methyl-                                                                     1,5-benzenediamine                                                            Dihydrochloride                                                               ______________________________________                                                          (E)          (F)                                                              Dose 50 μL/kg                                                                           IOP.sup.1                                                        50% sleeptime                                                                              hrs                                                              pro. in mice tested                                                                        dura-                                                            Na Hexobarbital                                                                            tion                                           ______________________________________                                        R.sub.1 = R.sub.2 = Cl;                                                                         77           5-6                                            R.sub.3 = R.sub.4 = H                                                         2,6-Dichloro-N--(2-                                                           imidazolidinylidene)-                                                         benezamine Free Base                                                          R.sub.1 = R.sub.2 = Cl;                                                                         1,250        7                                              R.sub.3 = H, R.sub.4 = NH.sub.2                                                                              7                                                                             5-6                                            2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-1,4-                                                     benzenediamine Dihydro-                                                       chloride                                                                      R.sub.1 = R.sub.2 = Cl;                                                                         2,300        7-8                                            R.sub.3 = H, R.sub.4 = NCOH                                                   N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-formamide Free Base                                                   R.sub.1 = R.sub.2 = Cl;                                                                         2,100        7                                              R.sub.3 = H, R.sub.4 = NCOCH.sub.3                                            N--[3,5-Dichloro-4-(2-                                                        imidazolidinylideneamino)-                                                    phenyl]-acetamide Hydrochloride                                               R.sub.1 = R.sub.2 = Cl;                                                                         10,000                                                      R.sub.3 = H, R.sub.4 = --OH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    phenol Hydrochloride                                                          R.sub.1 = R.sub.2 = Cl;                                                                         175          7                                              R.sub.3 = --NH.sub.2, R.sub.4 = H                                             2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Hydrochloride                                                                 R.sub.1 = R.sub.2 = Cl;                                                                         1,080        5-6                                            R.sub.3 = H, R.sub.4 = --CH.sub.2 --OH                                        3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenemethanol                                                               Hydrochloride                                                                 R.sub.1 = R.sub.2 =  Cl;                                                                        12,150                                                      R.sub.3 = H, R.sub.4 = COOH                                                   3,5-Dichloro-4-(2-                                                            imidazolidinylidene                                                           amino)-benzoic Acid                                                           R.sub.1 = R.sub.2 = Cl;                                                                         4,050        5-6                                            R.sub.3 = H, R.sub.4 = CO.sub.2 C.sub.2 H.sub.5                                                              4-5                                            3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzoic Acid Ethyl Ester                                                      R.sub.1 = R.sub.2 = Cl;                                                                         2,950                                                       R.sub.3 = H, R.sub.4 = N(CH.sub.3).sub.2                                      2,6-Dichloro-N.sup.1 --(2-                                                    imidazolidinylidene)-N.sup.4, N.sup.4-                                        dimethyl-1,4-benzene-                                                         diamine Dihydrochloride                                                       R.sub.1 = R.sub.2 = ethyl;                                                                      420                                                         R.sub.3 = H, R.sub.4 = H                                                      2,6-Diethyl-N--(2-                                                            imidazolidinylidene)-                                                         benzamine Free Base                                                           R.sub.1 = R.sub.2 = ethyl;                                                                      340                                                         R.sub.3 = H, R.sub.4 = NH.sub.2                                               2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,4-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = ethyl;                                                                      --                                                          R.sub.3 = H, R.sub.4 = NCOCH.sub.3                                            N--[2,6-Diethyl-4-(2-                                                         imidazolidinylideneamino)-                                                    phenyl]-acetamide                                                             Hydrochloride                                                                 R.sub.1 = R.sub.2 1,100hyl;                                                   R.sub.3 = --NH.sub.2, R.sub.4 = H                                             2,6-Diethyl-N.sup.1 --(2-                                                     imidazolidinylidene)-                                                         1,3-benzenediamine                                                            Dihydrochloride                                                               R.sub.1 = R.sub.2 = Cl;                                                                         4,050                                                       R.sub.3 = H, R.sub.4 = --CN                                                   4-Cyano-2,6-dichloro-                                                         N--(2-imidazolidinylidene)-                                                   benzamine                                                                     R.sub.1 = R.sub.2 = Cl;                                                                         4,050                                                       R.sub.3 = H, R.sub.4 = --CONH.sub.2                                           3,5-Dichloro-4-(2-                                                            imidazolidinylideneamino)-                                                    benzenecarboxamide Free Base                                                  R.sub.1 = Cl; R.sub.2 = H; R.sub.3 = NH.sub.2 ;                               R.sub.4 = CH.sub.3                                                            6-Chloro-N.sup.1 = (2-                                                        imidazolidinylidene)-                                                         4-methyl-                                                                     1,3-benzenediamine                                                            Dihydrochloride                                                               ______________________________________                                         .sup.1 In testing at present in the steroid rabbit model. Duration of         action in the Steroid rabbit model in hours, versus control, statisticall     significant 95% confidence.                                                   .sup.2 Dose % IOP effect at 0.25% (50 μL) topical.                         .sup.3 Dose % IOP effect at 0.125% (50 μL) topical.                   

The data in Columns A, B, and C of TABLE I, which are expressed as apercent lowering of IOP from control values, as well as the data inColumns D, E, and F of TABLE I establish that the disclosed compoundsare capable of lowering IOP at therapeutic levels which do not effectsystemic blood pressure or express any overt central nervous system sideeffects such as sedation.

It should be understood that while certain preferred embodiments of thepresent invention have been illustrated and described, variousmodifications thereof will become apparent to those skilled in the art.Accordingly, the scope of the present invention should be defined by theappended claims and equivalents thereof.

Various features of the invention are set forthin in the followingclaims.

What is claimed is:
 1. A method for lowering intraocular pressure comprising topically applying to the eye an effective amount for lowering such intraocular pressure of a 2-(trisubstituted phenylimino)-imidazoline, or a pharmaceutically acceptable salt thereof, having the formula ##STR64## where R₁, R₂, R₃ and R₄ are defined in accordance with either I, II, or III as follows:I. R₁ =R₂ =methyl, ethyl, trifluoromethyl, chloro or bromo. R₁ ≠R₂ and each=methyl, ethyl, trifluoromethyl, fluoro, chloro and bromo, one of R₃ and R₄ is H and the other is selected from ##STR65## R₅ ≠R₆ =H or lower alkyl, R₅ =R₆ and each=H, lower alkyl, R₇ =H, lower alkyl 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl, the sum of the carbon atoms in R₅ and R₆ or R₅ and R₇ being 4 or less, or ##STR66## R₈ =lower alkyl; II. R₁ =methyl, ethyl, trifluoromethyl, chloro or bromo, R₂ =H, R₃ =is selected from ##STR67## R₄ =methyl, chloro or bromo R₉ =H or lower alkyl, R₁₀ =H, lower alkyl, 2-hydroxymethyl, 2-hydroxypropyl or 3-hydroxypropyl, the sum of the carbon atoms in R₉ and R₁₀ being 4 or less; III. In no event shall said 2-(trisubstituted phenylimino)-imidazoline have the formula: ##STR68##
 2. A method in accordance with claim 1 wherein the 2-(trisubstituted phenylimino)-imidazoline or salt is topically applied to the eye in a pharmaceutically acceptable vehicle.
 3. A method in accordance with claim 2 wherein the concentration of the 2-(trisubstituted phenylimino)-imidazoline or salt is selected such that intraocular pressure is reduced without significantly affecting the central nervous system.
 4. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 2,6-Dichloro-N¹ -(2-imidazolidinylidene)-1,4-benzenediamine having the structure: ##STR69## or pharmaceutically acceptable salt thereof.
 5. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 2,6-Dichloro-N¹ -(2imidazolidinylidene)-1,3-benzenediamine having the structure: ##STR70## or pharmaceutically acceptable salt thereof.
 6. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 2,6-Diethyl-N¹ -(2-imidazolidinylidene)-1,4-benzenediamine having the structure of: ##STR71## or pharmaceutically acceptable salt thereof.
 7. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is N-[3,5-Diethyl-4-(2-imidazolidinyleneamino)-phenyl]-acetamidne having the structure: ##STR72## or pharmaceutically acceptable salt thereof.
 8. A method in accordance with claim 3 wherein the 2(trisubstituted phenylimino)-imidazoline is 3,5-Dichloro-4-(2-imidazolidinylideneamino)-phenol and esters thereof having the structure: ##STR73## or pharmaceutically acceptable salt thereof.
 9. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 3-chloro-5-methyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester having the structure: ##STR74## or pharmaceutically acceptable salt thereof.
 10. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 3-chloro-5-ethyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester having the structure: ##STR75## or pharmaceutically acceptable salt thereof.
 11. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is N-[3-chloro-5methyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamide having the structure: ##STR76## or pharmaceutically acceptable salt thereof.
 12. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 2 chloro-6methyl-N¹ -(2-imidazolidinylidene)-1,4 benzenediamine having the structure: ##STR77## or pharmaceutically acceptable salt thereof.
 13. A method in accordance with claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 2-chloro-6ethyl-N¹ -(2-imidazolidinylidene)-1,4 benzenediamine having the structure: ##STR78## or pharmaceutically acceptable salt thereof.
 14. A method in accordance wtih claim 3 wherein the 2-(trisubstituted phenylimino)-imidazoline is 3-chloro-5methyl-4-(2-imidazolidinylideneamino)-benzenecarboxamide having the structure: ##STR79## or pharmaceutically acceptable salt thereof. 